Bis-(amino alkoxy phenyl)sulfides, sulfoxides and sulfones



United States Patent 3,332,958 BIS-(AMINO ALKOXY PHENYDSULFIDES, SULFOXIDES AND SULFONES Lincoln Harvey Werner, Summit, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 22, 1965, Ser. No. 450,176 11 Claims. (Cl. 260295) This is a continuation-in-part of my application Ser. No. 418,279, filed Dec. 14, 1964, which in turn is a continuation-in-part of my application Ser. No. 362,937, filed April 27, 1964, now abandoned.

The present invention concerns bis-aryl-sulfides. More particularly, it relates to compounds of the formula Ar XAr in which X stands for thio (S), sulfinyl (S0) or sulfonyl (S0 and each of the groups Ar and Ar is monocyclic carbocyclic aryl substituted by N-substituted amino-lower alkyl-oxy, in which the N-substituted amino group is separated from oxy by at least two carbon atoms, salts, N-oxides, salts of N-oxides and quaternary ammonium compounds thereof, as well as a procedure for the preparation of such compounds. The above compounds are, more especially, represented by the formula Ar -XAr in which X and Ar have the above-given meaning.

The monocyclic carbocyclic aryl groups Ar and Ar have preferably one N-substituted amino-lower alkyl-oxy substituent. Such group may substitute any of the positions available for substitution; it preferably substitutes the 4-position. Ar and Ar may be otherwise unsubstituted or may contain one or more than one additional substituent, which may be attached to any position available for additional substituents. These are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl or Z-methyl-butyl-(Z), or halogeno, e.g. fluoro, chloro or bromo.

The N-substituted amino-lower alkyl-oxy substituent may be represented by the formula O(C,,H n)Am, in which the portion -(C ,H2n)- stands for lower alkylene having at least two carbon atoms (i.e. the letter 11 is an integer greater than one) and separating the N-substituted amino group Am from the oxygen atom by at least two carbon atoms. a

The portion --(C,,H stands for lower alkylene, which has preferably from two to three carbon atoms (n=2 or 3) and separates Am from the oxygen atom by at least two, preferably by two to three carbon atoms. Such alkylene group, for example, is l,2'ethylene, 1,2-, 2,3- or 1,3-propylene, as well as 1,3-, 2,3-, 3,4- or 1,4-butylene, 1,4- or 1,5-pentylene, 1,5- or 1,6-hexylene or 1,7-heptylene.

An N-substituted amino group Am is an N-monosubstituted or an N,N-disubstituted amino group, in which the substituents are organic groups having preferably from one to ten carbon atoms. Such groups are, for example, aliphatic radicals, especially lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl or neopentyl, cycloaliphatic or cycloaliphatic-aliphatic radicals, such as cycloalkyl or cycloalkyl-lower alkyl having from three to seven, preferably five or six ring carbon atoms, e.g. cyclopentyl or cyclohexyl, cyclopentylmethyl or 2-cyclohexylethyl, carbocyclic aryl radicals, such as monocycli-c carbocyclic aryl, e.g. phenyl, carbocyclic aryl-aliphatic radicals, such as monocyclic carbocyclic aryl-lower alkyl, for example, phenyl-lower alkyl, e.g. benzyl, l-phenylethyl or Z-phenylethyl, or lower alkyl having funtional groups, such as hydroxy-lower alkyl, e.g. Z-hydroxyethyl, lower-alkoxylower alkyl, e.g. Z-methoxyethyl or Z-ethoxy ethyl.

N-monosubstituted amino groups Am are, for example, lower alkylamino, e.g. methylamino, ethylamino or n-propylamino, cycloalkylamino, e.g. cyclopentylamino or cyclohexylamino, cycloalkyl-lower alkyl-amino, e.g. cyclopentylmethylamino or 2-cyclohexylethylamino, monocyclic carbocyclic aryl-lower alkylamino, such as phenyllower alkylamino, e.g. benzylamino or 2-phenylethylamino.

N,N-disubstituted amino groups Am are primarily dilower alkylamino, e.g. dimethylamino, N-methyl-N-ethylamino, diethylamino, di-n-propyla-mino, di-isopropylamino or di-n-butylamino, N-cycloalkyl-N-lower alkylamino, e.g. N-cyclopentyl-N-methylamino, N-cyclohexyl- N-methylamino or N-cyclohexyl-N-ethylamino, N-lower alkyl-N-phenyl-lower alkylamino, e.g. N-methyl-N-benzyl-amino, N-ethyl-N-benzyl-amino, N-ethyl-N-(l-phenylethyl)-amino or N-methyl-N-(Z-phenylethylkamino, as well as N,N-disubstituted amino groups, in which the substituents carry functional groups, for example, N-hydroxy-lower alkyl-N-lower alkylamino or N,N-di- (hydroxy-lower alkyl)-amino in which hydroxyl is separated from the amino-nitrogen by at least two, preferably by two to three, carbon atoms, e.g. N-(2-hydroxyethyl)- N-methylamino or N,N-di-(2-hydroxyethyl)-amino.

In an N,N-disubstituted amino group Am the two substituents may also be taken together and form a divalent radical; such groups are, for example, alkyleneimino, in which alkylene has from four to eight carbon atoms, such as pyrrolidino or Z-methyl-pyrrolidino, piperidino, 2-methy1-piperidino or 4-methyl-piperidino, 1,6-hexyleneimino or 1,7-heptyleneimino, piperazino or, particularly, 4-lower alkyl-piperazino, e.g. 4-methyl-piperazino or 4-ethyl-piperazino, 4-morpholino or 4-thiamorpholino.

Salts of the compounds of this invention are acid addition salts, especially those with pharmaceutically acceptable acids such as inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric or phosphoric acid, or organic acids, preferably carboxylic or sulfonic acids, e.g. acetic, propionic, pivalic, glycolic, lactic, malonic, succinic, maleic, hydroxymaleic, malic, tartaric, citric, benzoic, salicylic, 2 acetoxybenzoic, nicotinic or isonicotinic acid, methane or ethane sulfonic, ethane, 1,2-disulfonic, Z-hydroxyethane sulfonic, p-toluene sulfonic or naphthalene 2-sulfonic acid. Other addition salts with acids may be useful as intermediates, for example, in the preparation of pharmaceutically acceptable acid addition salts or in the purification of the free compounds, as well as for identification or characterization purposes. Salts, which are prepared primarily for the latter, are, for example, those with certain inorganic acids, e.g. perchloric acid, phosphotungstic, phosphomolybdic, chloroplatinic o1 Reinecke acid or with acidic organic nitrocompounds e.g. picric, picrolonic or flavianic acid. Monoor polysalts may be formed depending on the number of saltforming groups and/or the conditions used for the salt formation.

Salts of the N-oxides of the aforementioned compounds, particularly the acid addition salts thereof are for example, those with the above-mentioned acids.

Quaternary ammonium derivatives of the compound: of this invention are those formed with reactive esters oi alcohols and strong inorganic or organic acids, particularly those wtih lower aliphatic halides, sulfates, or organit sulfonates, such as lower alkyl halides, e.g. methyl, ethyl n propyl or isopropyl chloride, bromide or iodide, di lower alkyl sulfates, e.g. dimethyl sulfate or diethyl sul fate, lower alkyl lower alkane sulfonates, e.g. methyl 0: ethyl methane sulfonate. Also included as quaternary am monium compounds are the corresponding quaternary ammonium hydroxides, and the quaternary ammoniun salts with acids other than hydrohalic, sulfuric or organit ;ulfonic acids, particularly those with the organic car- )oxylic acids mentioned hereinabove.

The new compounds of this invention have anti-inflamnatory properties. They are, therefore, useful as antinflammatory agents in place of certain corticosteroids, :.g. cortisone or hydrocortisone, in the treatment of tissue nfiammations, such as arthritic intlammations.

The compounds of this invention also have anti-paraitic, particularly taeniacidal properties, and are, thereore, useful as taeniacides in the treatment of tapeworm nfections, caused, for example, by Hymenolepis nana, )ypilidium cranium or T aenia pisiformis or Moniezia exansa.

Particularly useful are the compounds of the formula Rb R 1 which X 'has the previously-given meaning, but stands 101'6 especially for thio, Am stands primarily for di- Jwer alkyl-amino, as well as alkyleneimino, in which lkylene has from four to seven carbon atoms, 4-morholino or 4-lower alkyl-piperazino, the portion :ands for alkylene having from two to five carbon atoms n'=2 to 5) and separates the group Am from the oxyen atom by at least two carbon atoms, and each of the roups R and R stands for hydrogen, lower alkyl or alogeno, and the acid addition salts thereof. Especially aluable are those compounds of the above formula, in hich the portion (C H stands for alkylene hav- .g from two to three carbon atoms and separates the roup Am from the oxygen atom by two to three carbon :oms, as well as the acid addition salts, particularly the Jarmaceutically acceptable acid addition salts, thereof. The compounds of the present invention are prepared :cording to methods known per se; for example, they are stained by converting in a compound of the formula r XAr in which X has the previously given caning, and each of the groups Ar and Ar is monoclic carbocyclic aryl substituted by R capable of being )nverted into N-substit-uted amino-lower alkyl-oxy, in hich N-substituted amino is separated from oxy by at ast two carbon atoms, or a salt thereof, the group R to said N-substituted amino-lower alkyl-oxy group and, desired, converting in a resulting compound the group into another group representing X, and/ or, if desired, nverting a resulting salt into the free compound or into other salt, and/or, if desired, converting a resulting mpound into an N-oxide or a quaternary ammonium mpound thereof, and/ or, if desired, converting a resultg free compound or an N-oxide into a salt thereof, vd/or, if desired, converting a quaternary ammonium mpound into another quaternary ammonium compound, d/or, if desired, separating a mixture of isomers into a single isomers. The above starting material, more especially, is rep- ;ented by the formula Ar XAr in which X and has the previously-given meaning. The conversion R into N-substituted amino-lower alkyl-oxy is carried tin one step or in stages. A particularly suitable group representing R is hynxyl; its conversion into N-substituted amino-lower :yl-oxy is carried out according to known procedures. ually, the starting material, in which each of the groups and Ar is substituted by hydroxyl, or preferably talt thereof, is reacted with a reactive ester of an N- )stituted amino-lower alkanol, particularly a compound the formula Am(C,,H )Y, in which Am and the rtion (C H have the previously-given mean- Am representing primarily an N,N-disubstituted ino group, and Y stands for a reactive esterified hydroxyl group. The latter is above all a hydroxyl group esterified with a strong mineral acid, such as a hydrohalic acid, e.g. hydrochloric or hydrobromic acid. It may also be a hydroxyl group esterified with a strong organic sulfonic acid, such as a lower alkane sulfonic acid, e.g. methane or ethane sulfonic acid, or a monocyclic carbocyclic aryl-sulfonic acid, e.g. p-toluene sulfonic acid.

As noted above, the starting material is preferably used in the form of a salt thereof. Such salt, for example, a metal salt, particularly an alkali metal salt, e.g. lithium, sodium or potassium salt, as well as an alkaline earth metal salt, or any other suitable salt, is formed, for example, by treatment of the starting material with a metal saltforming reagent, such as an alkali metal hydride or amide, e.g. lithium hydride, sodium hydride, sodium amide or potassium amide, an alkali metal or alkaline earth metal lower alkoxide, e.g. lithium, sodium, potassium or barium methoxide, ethoxide, or tertiary butoxide, or an alkali metal compound of a hydrocarbon, e.g. butyl lithium, phenyl lithium or phenyl sodium. The preparation of the salt is usually carried out in the presence of an inert solvent, for example, a hydrocarbon, e.g. hexane, benzene, toluene or xylene, an ether, e.g. diethyl ether, p-dioxane, tetrahydrofuran or diet'hyleneglycol, or especially a carboxylic acid amide, e.g. dimethylformamide, or any other suitable solvent, such as a lower alkanol, e.g. methanol or ethanol or a solvent mixture, if necessary, while cooling or at an elevated temperature, and/ or in the atmosphere of an inert gas.

The reaction of the starting material, particularly a metal compound thereof, with the reactive ester of an N-substituted amino-lower alkanol is carried out in the presence of a suitable diluent, for example, in the solvent or solvent mixture used for the preparation of a metal compound, if necessary, while cooling or at an elevated temperature, and/ or, in the atmosphere of an inert gas, e.g. nitrogen. Formation of the metal compound of the starting material may also be achieved in situ; for example, the free starting material and the reactive ester of the N-substituted amino-lower alkanol may be reacted in the presence of a salt-forming reagent, for example, an alkali metal carbonate or an alkaline earth metal carbonate.

The conversion of hydroxyl representing R into N- substituted amino-lower alkyl-oxy may also be achieved by treating the corresponding starting material with an N-substituted amino-lower alkanol, particularly an N,N- disubstituted amino-lower alkanol, in the presence of a disubstituted carbonate. The latter is, for example, a di-aryl carbonate, e.g. diphenyl carbonate, or more particularly, a di-lower alkyl carbonate, e.g. dimethyl carbonate, ethyl methyl carbonate, diethyl carbonate or dibutyl carbonate. The reaction is carried out at an elevated temperature, for example, between about and about 210, preferably between about 180 and about 200, and, if desired, in the presence of a transesterification catalyst enhancing the rate of the reaction, such as sodium, potassium, sodium carbonate, potassium carbonate or sodium aluminate, a metal lower alkoxide, e.g. sodium ethoxide or titanium butoxide, or any other analogous reagent. The reaction is usually performed in the absence of an additional solvent and in an excess of the di-substituted car-- bonate serving as the diluent, but may also be carried out in the presence of a further solvent or solvent mixture, if necessary, in a closed vessel and/ or in the atmosphere of an inert gas, e.g. nitrogen.

Another group R capable of being converted into N- substituted amino-lower alkyloxy is the group of the formula -OC(=O)-Z, in which Z represents halogeno or etherified hydroxyl. The group Z is particularly lower alkoxy, e.g. methoxy, ethoxy or n-butoxy, as well as phenoxy or any other analogous etherified hydroxyl group, whereas halogeno, representing Z, is particularly chloro, as well as bromo. Upon reacting a starting material, in which each of the groups Ar and Ar is substituted by said group -OC(=O)-Z, with an N- substituted amino-lower alkanol, particularly an N,N-disubstituted amino-lower alkanol, the compounds of the invention are formed. The reaction is carried out under the previously-described conditions, i.e. at an elevated temperature, preferably between 180 and 200, and, if desired, in the presence of a transesterification reagent, such as one of those previously described; the reaction is preferably performed in the absence of a diluent, but may also be carried out in the presence of a solvent or solvent mixture, if necessary, in the atmosphere of an inert gas, e.g. nitrogen. Y

A further group R capable of being converted into N-substituted amino-lower alkyl-oxy is a reactive esterified hydroxy-lower alkyl-oxy group. The latter is particularly a group of the formula -O(C H2n) Y, in which Y and the portion -'(C H have the previously-given meaning. The reactive esterified hydroxyl group Y is primarily halogeno, particularly chloro; it may also be a suitable organic sulfonyloxy group, such as one of those mentioned above.

A starting material, in which each of the monocyclic carbocyclic aryl groups Ar and Ar is substituted by a reactive esterified hydroxy-lower alkyl-oxy group, is reacted with an N-substituted amine, having preferably the formula H-Am, in which Arn has the above-given meaning, to yield the desired compound. The reaction is preferably carried out in such manner, that an excess of the amine or of any other suitable acid-neutralizing agent, e.g. potassium carbonate, is present to neutralize the generated acid. If desired, the reaction mixture is diluted with a suitable inert solvent or solvent mixture; if necessary, the reaction is carried out while cooling or at an elevated temperature, and/or in the atmosphere of an inert gas, e.g. nitrogen, and/or in a closed vessel.

The starting material used in the above procedure is known and prepared according to known methods. Thus, a bis-(monocyclic carbocyclic aryl)-sulfide is obtained, for example, by reacting a phenol with sulfur dichloride in the presence of carbon disulfide. In a resulting bis- (monocyclic carbocyclic aryl)-sulfide, the thio group may be converted into a sulfinyl group or a sulfonyl group according to known oxidation methods; the oxidation of the thio group into a sulfinyl group is carried out by oxidation with hydrogen peroxide in the presence of glacial acetic acid while cooling, with an organic peracid, e.g. peracetic, perbenzoic or monoperphthalic acid, at low tempeartures, with chromic acid in the presence of acetic acid and under mild conditions, with nitric acid or any other suitable reagent, whereas its conversion into the sulfonyl group is performed by treatment with hydrogen peroxide or organic per-acids at room temperature or preferably at elevated temperatures, with potassium permanganate in the presence of an acid, e.g. acetic or diluted sulfuric acid. Bis-(monocyclic carbocyclic aryl) sulfoxides may also be obtained by reacting a phenol with aluminum chloride in the presence of carbon disulfide and thionyl chloride, whereas a bis-(monocyclic carbocyclic aryl)-sulfone may be obtained by reacting the phenol with oleum, i.e. concentrated sulfuric acid containing sulfur trioxide. A resulting bis-(monocyclic carbocyclic aryl)-sulfoxide may be converted into the corresponding sulfide compound by reduction, for example, with zinc and acetic acid or any other suitable reduction procedure.

In a starting material, in which each of the monocyclic carbocyclic aryl groups Ar and Ar is substituted by hydroxyl, the latter may be converted into the group -OC(=O)Z in which Z has the previously-given meaning, for example, according to any method suitable for the esterification of a phenolic hydroxyl group, such as formation of an alkali metal compound of the phenolic intermediate and reaction of the latter with an ester of the acid of the formula HO-C(=O)-Z or the halide thereof.

In addition, a starting material Ar X-Ar in which each of Ar and Ar is substituted by hydroxyl, the latter may be converted into a reactive esterified hydroxy-lower alkyl-oxy group by treating said starting material or a salt thereof with a corresponding lower alkylene-oxide, a halogeno-lower alkanol or a lower alkylene halide, for example, a chloro-lower alkyl bromide, and, if necessary, converting in a resulting hydroxy-lower alkyloxy compound the hydroxyl group into an esterified hydroxyl group according to known methods, for example, by treatment with a thionyl halide, e.g. thionyl chloride, a phosphorus halide, e.g. phosphorus tribromide or an organic sulfonic acid halide, e.g. mesyl or tosyl chloride, or any other suitable method.

In a resulting compound of the formula Ar -X-Ar in which Ar Ar and X have the previously-given meaning, a group X may be converted into another group representing X. This conversion is carried out according to known methods, such as those previously described for the starting material, preferably with oxidation reagents that do not favor the formation of oxidative degradation products or N-oxides.

A resulting acid addition salt is converted into the free base, for example, by treating it with an alkaline reagent, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate, ammonia or a suitable hydroxyl ion exchange resin.

A resulting acid addition salt can be converted into another salt according to known methods, for example, by treatment with a suitable anion exchange preparation. Furthermore, an acid addition salt, particularly an addition salt with an inorganic acid, may be converted into another acid addition salt, for example, by reacting it with a suitable metal, e.g. sodium, barium or silver, salt of an acid, preferably in the presence of a diluent in which a resulting inorganic salt is insoluble and is thus removed from the reaction medium.

A free base is converted into an acid addition salt thereof according to known methods, for example, by reacting it or a solution thereof in a suitable solvent or solvent mixture with the acid or a solution thereof, or with a suitable anion exchange preparation, and isolating the desired salt. A salt may be obtained in the form of a hydrate thereof or may include solvent of crystallization.

An N-oxide of the compounds of this invention is prepared according to known methods, for example, by treating the free base with a suitable N-oxidizing reagent, such as hydrogen peroxide, ozone or a peracid, e.g. peracetic, perbenzoic, monoperphthalic or persul'furic acid, in the presence of a suitable inert diluent. During the formation of an N-oxide, a thio or a sulfinyl group representing the group X of a resulting compound, may be converted into sulffinyl and/ or sulfonyl, respectively. An N-oxide is converted into an acid addition salt thereof according to the above procedure.

Quaternary ammonium derivatives of the compounds of this invention are obtained according to known methods, for example, by reacting the base with the reactive ester of an alcohol and a strong acid, such as, for example, with one of the lower alkyl halides, di-lower alkyl sulfates, lower alkyl organic sulfonates or phenyl-lower alkyl halides described above. The quaternizing reaction is performed in the presence or absence of a solvent, While cooling or at an elevated temperature, if necessary, in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen.

Resulting quaternary ammonium compounds may be converted into other quaternary ammonium compounds, such as the quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with a hydroxyl ion exchange preparation or any other suitable method. A quaternary ammonium hy- 7 lroxide is converted into a quaternary ammonium salt y reacting the former with a suitable acid. A quaternary immonium salt is also converted directly into another uaternary ammonium salt; for example, a quaternary immonium iodide, when reacted with freshly prepared :ilver chloride or with hydrochloric acid in anhydrous nethanol, yields the desired quaternary ammonium chlo- 'ide, or a quaternary ammonium salt, when treated with t-suitable anion exchange preparation, can be converted nto another quaternary ammonium salt. A quaternary tmmoniurn compound may be obtained in the form of a iydrate thereof or may contain solvent of crystallization.

A mixture of resulting isomeric compounds may be eparated into the single isomers. For example, a mixture )f diastereoisomers is separated into the individual acemic compounds on the basis of physico-chemical diferences, such as solubility, for example, by fractional rystallization, as well as by fractional distillation. t-acemates are resolved into the optically active forms .ccording to known resolution procedures, for example, ty forming a salt of the free racemic base with one of he optically active forms of an acid containing an asymaetric carbon atom. A resulting mixture of salts of the ptically active acid with the antipodes of the base acemate is separated into the single salts on the basis of hysico-chemical differences, for example, by fractional rystallization. From a resulting salt, the free and opcally active base is obtained according to the method escribed above, and a free and optically active base an be converted into its acid addition salt, N-oxide, salt f an N-oxide or quaternary ammonium compound acording to the procedures described above.

The invention also comprises any modification of the rocess wherein a compound formed as an intermediate t-any stage of the process, is used as starting material nd the remaining step(s) of the process is(are) carried at, as Well as any new intermediates.

In the process of this invention such starting materials re preferably used which lead to final products mentioned I the beginning as preferred embodiments of the invenon.

The compounds of this invention are useful in the form E pharmaceutical compositions suitable for enteral, e.g. .al, parenteral or topical use; essentially, they comprise pharmacologically effective amount of one of the com- )unds of this invention in admixture With a pharma- :utically acceptable, organic or inorganic, solid or liquid trrier, which usually represents the major portion by eight of such compositions. These preparations are in lid form, for example, as capsules, tablets or dragees,

liquid form, for example, as solutions or suspensions,

' in the form of emulsions, e.g. salves or creams. Suitae carrier materials, are, for example, starches, e.g. corn arch, wheat starch or rice starch, sugars, e.g. lactose, ucose or sucrose, stearic acid or salts thereof, eg, agnesium stearate or calcium stearate, benzyl alcohol, :aryl alcohol, cetyl alcohol, petrolatum, talc, gums, acia, tragacanth, sodium lauryl sulfate, polyalkylene ycols or propylene glycol. The quantity and the nature the carrier ingredients can vary Widely and depend, ter alia, upon the desired physical appearance or size the composition or method of manufacture. Encapsulatn may be effected by using, if desired, the same excip- 1ts as those for tables. If necessary, the compositions ay contain other auxiliary substances, such as preservg, stabilizing, Wetting or emulsifying agents, salts for rying the osmotic pressure or butters. They may also ntain, in combination, other pharmacologically useful bstances. The compounding of the formulations is genally carried out in the manner normally employed in art, i.e. by manufacturing a mixture or a granulate. 1y compatible color, approved and certified under the ovisions of the Federal Food, Drug and Cosmetic Law 1y be used for aesthetic purposes or as a means of :ntification.

is The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

EXAMPLE 1 To a solution of 10.8 g. of bis-(4-iydroxy-2-rnethyl-5- tert. butyl-phenyl)-sulfide in a mixture of 50 ml. of toluene and 30 ml. of dimethylformamide is added in portions 2.7 g. of a 53% suspension of sodium hydride in mineral oil, while maintaining an atmosphere of nitrogen. After stirring for ten minutes, a solution of 8.0 g. of 3-dimethylamino-propyl chloride in toluene is added, and the reaction mixture is heated to 60 for 1 /2 hours, and then at for 4 /2 hours. After cooling, the inorganic precipitate is filtered ofi and the filtrate is concentrated under reduced pressure. The residue is dissolved in diethyl ether, the organic solution is Washed with Water, dried and evaporated to dryness. The residue is dissolved in ethyl acetate, and the solution containing the bis-[4- (3-dimethylamino-propyl)-oxy 2 methyI-S-tert. butylphenylJ-sulfide of the formula is treated with a solution of hydrogen chloride in ethyl acetate, and the resulting crystalline bis-[4-(3-dimethylamino-propyl) -oxy-2-methyl-5-tert. butyl-phenyl] -sulfide dihydrochloride is filtered oh and recrystallized twice from a mixture of isopropanol and ethyl acetate, MP. 209-211".

Bis-[4-(3-dimethylamino-propyl)-oxy 2 methyl-5- tert. butyl-phenylJ-sulfide, when reacted with picric acid or With methyl iodide, yields the bis-[4-(3-dimethylaminopropyl)-oxy-2-methyl-5-tert. butyl-phenylJ-sulfide picrate and the bis-[4-(3-dimethylamino-propyl)-oxy 2 methyl- S-tert. butyl-phenyH-sulfide dimethiodide, respectively.

EXAMPLE 2 By reacting 10.8 g. of bis-(4-hydroxy-2-methyl-S-tert. butyl-phenyl)-sulfide in a mixture of 50 ml. of toluene and 30 ml. of dimethylformamide with 2.7 g. of a 53% suspension of sodium hydride in mineral oil and then with a solution of 9.8 g. of l-(2-chloro-ethyl)-piperidine in toluene according to the procedure described in Example 1, yields the bis-[4(2-piperidino-ethyl)-oxy-2- methyl-S-tert. butyl-phenyH-sulfide of the formula which is converted into the dihydrochloride with a solution of hydrogen chloride in ethyl acetate, M.P. 270 (decomposition) after recrystallization from a mixture of ethanol and ethyl acetate.

EXAMPLE 3 To a solution of 16.2 g. of bis-(4-hydroxy-2-methyl-5- tert. butyl-phenyl)-sulfide in 45 ml. of dimethylformamide and 75 ml. of toluene is added 4.0 g. of a 53% suspension of sodium hydride in mineral oil While stirring and maintaining an atmosphere of nitrogen, and then a solution of 10.75 g. of Z-dimethylamino-ethyl chloride in toluene. The reaction mixture is stirred for six hours at 60, and is then allowed to stand overnight. After filtering, the solution is concentrated under reduced pressure; the residue is dissolved in diethyl ether, the organic solution is Washed with Water, dried and concentrated under reduced pressure. The residue is dissolved in ethyl acetate, and the solution, containing the bis-[4-(2-dimethylaminoethyl)-Xy-2-methyl-5-tert. butyl-phenyl]-sulfide of the formula w ah K ah is treated with hydrogen chloride in ethyl acetate. The resulting crystalline bis-[4-(Z-dimethylamino-ethyl)-oxy-2- methyl-S-tert. butyl-phenyl1-sulfide dihydrochloride is one hour, 8.95 g.

of diethylarnino-ethyl chloride, diluted residue is taken up in diethyl ether and Water, the ethereal layer Washed with water, dried and evaporated. The residue is dissolved in ethyl acetate and the solution mixed with a solution of hydrogen chloride in ethyl acetate. The

mula

so obtained bis- [4- (Z-diethylamino-ethyl) -oxy-2-methyl- S-tert. butyl-phenyH-sulfide dihydrochloride of the forfiltered off and recrystallized from a mixture of ethanol 30 is filtered olf and recrystallized from methyl ethyl ketoneethylacetate; M.P. 192-193".

and ethyl acetate, M.P. 270-273.

EXAMPLE 4 Other compounds of this invention, which are prepared for example,

EXAMPLE 6 diethylamino-propyl chloride, the bis-[4-(3--diethylamino Starting Material Reagents Product Bis- (4-hydroxy-pheny1)sulfide;

Do. Do.

1(ggzgeloheirylt-hydroxy--methyl-pl1enyl)- Bis-(2,(idibenzyl-khydroxy-phenyl)-su1fide Bis- (2,6-dl-lsopropyl-4-hydroxy-phenyD-sulfide.

Bis-(3,5-dichloro-4-hydroxy-phenyl)-sulfide Bis-(2,6-diehloro-i'hydroxy-phenyl)-sulfide Bls-(2-ethyl-4-hydroxy-phenyl)-sulfide Bis-(2-diethylamino-methyl-3,G'dimethyH-hydroxy-phenyD-sulfide.

Bis= (4-hydroxy-pl1e11yl)-sulfoxide Bis-(4-hydroxy-2-methyl-5-tertiary butylphenyD-sulfoxide. Bis-(4-hydroxy-phenyl)-sult0ne Bis-(4-hydroxy-Z-methyl-S-tertiary butylphenyD-sulfone. Bis-(3,4-dihydroxy ohenyl)sulfide Z-diethylamino-ethyl chloride plus NaH 1- (2-chlor0-ethyl)-pyrrolidlne plus NaH S-dimethylaminopropyl chloride plus NaH 2-diethylamino-ethyl chloride plus NaH 3-dimetl1ylamino-pr0pyl chloride plus NaH.

l-(3-chloro-ethyl)-piperidine plus NaH 3-dimethylamino-propyl chloride plus NaH Z-diethylaminoethyl chloride plus NaH n-Pl'opylamine EXAMPLE 5 To a mixture of 10.8 g. of bis-(4-hydroxy-2-rnethy1-5- tert. butyl-phenyl)-sulfide, ml. of dimethylformamide propyl)-oxy-2-methyl-5-tert. butyl-phenyljl-sulfide dihydrochloride of the formula is obtained; it melts after recrystallization from isopropaand ml. of toluene, 2.7 g. of a 53% suspension of sodium hydride in mineral oil is added keeping the Whole under nitrogen. After stirring for about while stirring and nol-ethyl acetate at 178-180".

EXAMPLE 7 Substituting in Example 5 the diethylamino-ethyl chlo- 1 i ride by 10.7 g. of 3-piperidino-propyl chloride and following the procedure given, the bis- [4-(3-piperidino-propyl)- oxy-2-methyl-5-tert. butyl-phenyl]-sulfide dihydrochloride of the formula i2 EXAMPLE Substituting in Example 9 the starting material by 9.0 g. of bis-(4-hydroxy-3-methyl-5-tert. butyl-phenyl)-sulfide and following the procedure given, the bis-[4-(3-dimethylls obtained; it melts after recrystallization from isoproqanol at 255-258.

EXAMPLE 8 2.25 g. of a 53% suspension of sodium hydride in nineral oil is gradually added with stirring to a mixture )f 8.9 g. of bis-(2-hydroxy-3,S-dichloro-phenyl)-sulfide,

lnder nitrogen. After stirring for one hour at room tem- Jerature a solution of 6.7 g. of B-dimethylamino-propyl :hloride in toluene is added and the whole heated for 8 tours to 7080. After cooling, the reaction mixture is vorked up as described in Example 5 in order to obtain he bis-[2-(S-dimethylamino-propyl)-oxy 3,5 dichloro- 1henyl]-sulfide dihydrochloride of the formula (Ill (I31 ml. of dimethylformamide and 45 ml. of toluene kept 25 l l (C 3) 2 2) 3-0 0 (CH2) s-N (0 Ha) 2- amino-propyl) -oxy-3-methyl-5 -te1't. butyl-phenyl] -sulfide dihydrochloride of the formula melting at 218-220", is obtained.

EXAMPLE 11 By reaction of 10. 8 g. of bis-(4-hydroxy-2-methyl-5- tert. butyl-phenyl)-sulfide in 30 ml. of dimethylformamide and ml. of toluene with 2.7 g. of a 53% suspension of sodium hydride in mineral oil followed by 11.7 g. of S-diethylamino-pentyl chloride in toluene according to the method desecribed in Example 5, the crude bis-[4-(5- diethylamino-pentyl)-oxy-2-methyl-5-tert. butyl phenyl] sulfide of the formula 'hich melts after recrystallization from isopropanol-ethyl :etate at 215-216.

EXAMPLE 9 2.25 g. of a 53% suspension of sodium hydride in r elting at 223225 after recrystallization from isoprotnol-ethy1 acetate.

N 03 C(CHa);

is obtained. It is converted into its dicitrate by combining an ethereal solution of the crude base with the equivalent amount of citric acid dissolved in ethyl acetate. The dicitrate precipitates and slowly solidifies. It is filtered off and after drying it softens on heating and begins to melt at EXAMPLE 12 A solution of 1.3 g. of 4,4'-methylene-bis-(3-hydroxy- 2-naphthoic acid) di-sodium salt (di-sodium pamoate) in 15 ml. of water is added to a solution of 1.81 g. of his- [4- 3 -dimethyl-amino-propyl -oxy-2-methyl-5-tert. butylphenylhsulfide dihydrochloride in 3 0 ml. of water. The pamoate precipitates, it is filtered ofi, slurried twice with warm water and dried; it melts with decomposition starting at EXAMPLE 13 A solution of 4.7 g. of his-[4-(3-dimethylaminopropyl)-oxy-2-methyl-5-tert. butyl-phenylJ-sulfide in 25 ml. of methanol is saturated with methyl chloride by bubbling it through the solution for 45 minutes. After standing for 4.5 hours the methanol is removed in vacuo and the residue treated with acetone whereupon it crystallizes. The so obtained bis-[4-(3-dimethylamino-propyl)- l3 l4 oxy-Z-methyl-S-tert. butyl-phenyl1-sulfide dimetho chlo- The reaction mixture is heated for 12 hours to 70-80 and ride of the formula after cooling it is filtered and concentrated in vacuo. The

(I311: (EH3 ea (Ha 0 -o(c112)31s(0113 3- 201 (X61193 X aM is filtered oil and dried; it melts at 253-255". residue is dissolved in diethyl ether, after washing with water. The ether Solution is dried and concentrated. The EXAMPLE 14 residue is dissolved in ethyl acetate and the dihydrochlo- TO a Solution of of Y Y-P y ride of the product is precipitated by adding a solution fone in m1. of dimethylformamide and 45 ml. of tol- 15 of hydrogen chloride in ethyl acetate. It crystallizes on uene, 2.25 g. of a 53% suspension of sodium hydride is treatment with ethanol. After recrystallization from ethstirred in under nitrogen and stirring is continued for one anol-ethyl acetate the bis-[4-(3-dimethylamino-propyl)- hour at room temperature. Thereupon a solution of 6.7 g. oxy-3-chlorophenyl]-sulfoxide dihydrochloride of the forof 3-dimethylamino-propyl chloride in 50 ml. of toluene mula is added and the reaction mixture stirred for 18 hours at melts at 203-205.

70 to 80. It is then filtered, concentrated under reduced EXAMPLE 17 pressure, the residue taken up in diethyl ether, the solution washed twice with Water, dried and evaporated in 9.0 g. of bis-(4-hydroxy-2-methyl-5-tert. butyl-phenyl)- vacuo. The residue is dissolved in ethyl acetate and mixed sulfide are dissolved in a mixture of 25 ml. dimethylwith asolution of hydrogen chloride in ethyl acetate. The formamide and 45 ml. of toluene. The flask is flushed precipitated bis [4 (3 dimethylamino-p-ropyl)-oxywith nitrogen while adding 2.25 g. of a 53% suspension phenyl]-sulfone dihydrochloride of the formula of sodium hydride in mineral oil. After stirring for one 3)2N(CH2)aO-S0\0(CH2)3N(Clash- 1101 is filtered ofi and recrystallized twice from ethanol-acehour at room temperature, a solution of 6.7 g. of 2-ditone; M.P. 216-218". methylamino-propyl chloride in 55 ml. of toluene is added. The reaction mixture is heated to 70-80", with stirring EXAMPLE 15 for 20 hours after cooling. It is then filtered and the filtrate Pwparatlon of capsules each contamlng gconcentrated in vacuo. The residue is dissolved in diethyl of the active ingredlent. ether, the solution washed twice with water, dried and concentrated. The residue is dissolved in ethyl acetate and a solution of hydrogen chloride in ethyl acetate is added. The precipitate formed is filtered off and recrystallized twice from a mixture of isopropanol-ethyl acetate. There Ingredients and procedure: G. 50

Bis- [4- 3-dimethylamino-propyl) -oxy-2- methyl-S-tert. butyl-phenyH-sulfide L dihydrochloride is obtained the bis-[4 (2 dimethy1aminopropoxy)-2- 't"'t 1000 methyl 5 tert. butyl-phenyl1-sulfide dihydrochloride agnesmm S Cara e monohydrate of the formula 3H3 CH (CHa):N?H-CHBOSOCH;(FHN(GHmZHCLHaO CH3 I l CH3 3)a a)a The ingredients are blended in a suitable mixer, sieved melting at 168 with decomposition.

through a No. 40 screen and again mixed. Portions weighing 0.65 g. each of the resulting mixture are filled into EXAMPLE 18 No. 0 capsules. To a solution of 6.9 g. of bis-(4-hydroxy-2,5-di-methyl- EXAMPLE 16 phenyl)-sulfide in 25 ml. of dimethylformamide and 45 ml. of toluene, 2.25 g. of a 53% suspension of sodium To a solution of 7.6 g. of bis-(4-hydroxy-3-chlorohydride in mineral oil is added with stirring under niphenyl)-sulfoxide in 25 ml. of dimethylformamide and 45 trogen. After one hour 6.7 g. of 3-dimethylamino-propyl ml. of toluene, 2.25 g. of a 53% suspension of sodium chloride, dissolved in 57 ml. of toluene, are added. The hydride in mineral oil is added. After stirring for one reaction mixture is heated to 7080 for 22 hours, cooled, hour at room temperature, a solution of 6.7 g. of 3-difiltered and concentrated under reduced pressure. The methylamino-propyl chloride in 50 ml. of toluene is added. residue is then dissolved in ethyl acetate and a solution CH CH l EXAMPLE 21 3.2 g. of bis-[4-(3-dimethylamino-propoxy -2-methyl-5- tert. butyl-phenyl]-sulfide are dissolved in ml. of isopropanol and a solution of 1.4 g. of maleic ,acid in 10.5 ml.

1elting at 240-242.

' EXAMPLE 19 By reacting 9.0 g. of bis-(4-hydroxy-2-methyl-5-tert. utyl-phenyl)-sulfide, dissolved in ml. of dimethyl- )rmamide and 45 ml. of toluene, with 2.25 g. of a 53% of isopropanol is added. The mixture is concentrated in vacuo and the residue triturated with diethyl ether, which 5 is decanted. A small volume of acetone is added and the product allowed to crystallize. There is obtained the his- [4 (3 dimethylamino propoxy) 2 methyl 5 tert. butyl-phenyl]-sulfide dimaleate of the formula lspension of sodium hydride in mineral oil, followed by 25 which melts at 142.

:action with a solution of 9.0 g. of 3-morpholino-propyl lloride in 88 ml. of toluene as described in Example 17, .e bis-[4-(3-morpholino-propoxy)-2-methyl-5-tert. butyl- 1enyl]-sulfide dihydrochloride of the formula CH CH a)a C( a)s obtained; M.P. 269 (decomp.).

EXAMPLE 20 By reacting 8.9 g. of bis-[2-hydroxy-5(1,1,3,3-tetraethyl-butyl)-phenyl]-sulfide, dissolved in 25 ml. of diethyl-formamide and ml. of toluene, with 1.8 g. of 53% suspension of sodium hydride in mineral oil, folwed by reaction with 5.4 g. of 3-dimethylamino-propyl ,loride dissolved in 46 ml. of toluene, following the con- 2.6 g. of bis-[4-(3-dimethylamino-propoxy)-2-methyl- 5-tert. butyl-phenylJ-sulfide are dissolved in 10 ml. of

ethyl acetate and a solution of 1.9 g. 3-hydroxy-2-naphthoic acid in 2 ml. of ethyl acetate is added. The reaction mixture is concentrated to a small volume and the desired salt is precipitated on addition of hexane. It is triturated several times with fresh hexane and finally with diethyl ether whereupon crystallization occurs. There is obtained the bis [4 (5 dimethylamino propoxy) 2 methyl- S-tert. butyl-phenyl] -sulfide di-( 3-hydroxy-2-naphthoate) ich foams at 140, but does not give a clear melt up melting at What is claimed is:

1. A member selected from the group consisting of a compound having the formula in which X is a member selected from the group consisting of thio, sulfinyl and sulfonyl, Am is a member selected from the group consisting of di-lower alkyl-amino, alkylene-imino in which alkylene has from four to seven carbon atoms, 4-morpholino and 4-lower alkyl-piperazino, the portion (C H ')-stands for alkylene having from two to five carbon atoms and separates the group A from the oxygen atom by at least two carbon atoms, and each of the groups R and R is a member selected from the group consisting of hydrogen, lower alkyl and halogeno. and acid addition salts. thereof.

2. A member selected from the group consisting of a compound having the formula Rb Rb in which Am is di-lower alnyl-amino, and the portion- (C 'H ')stands for alkylene having from two to three carbon atoms and separates the group Am from the oxygen atom by two to three carbon atoms, and each of the groups R and- R is .a member selected from the group consisting of hydrogen, lower alkyl and halogeno, and acid addition salts thereof.

3. A member selected from the group consisting of his [4 (3 dimethylamino propoxy) 3 methyl 5- tert. butyl-phenyl1-sulfide and an acid addition salt thereof.

4. A bis [4 (3 dimethylamino propoxy) 2- methyl-S-tert. butyl-phenyl]-sulfide dimetho-halide.

5. A member selected from the group consisting of bis [4 (3 dimethylamino propoxy) phenyl] sulfone and an acid addition salt thereof.

6. A member selected from the group consisting of bis- [4 (3 dimethylamino propoxy) 3 chloro phenyl]- sulfoxide and an acid addition salt thereof.

7. A member selected from the group consisting of his- [4 (3 dimethylamino propoxy) 2,5 dimethylphenyH-sulfide and an acid addition salt thereof.

8. A member selected from the group consisting of a compound having the formula in which X is a member selected from the group consisting of thio, sulfinyl and sulfonyl, each of Ar and Ar is a member selected from the group consisting of phenylene and phenylene substituted by at most 2 members selected from the group consisting of lower alkyl and halogeno, each of C H and C H is lower alkylene with 2 to 7 carbon atoms and separating the groups Am from the oxygen atoms by at least two carbon atoms and each of Am and Am is a member selected from the group consisting of lower alkylamino, di-lower alkyl-amino, cycloalkylamino, cycloalkyl-lower alkylamino and N-cycloalkyl-N-lower alkylamino in which cycloalkyl has 3 to 7 ring-carbon atoms, N-lower alkyl-N-phenyl-lower alkylamino, N-hydroxy-lower alkyl-N-lower alkylamino, N,N- di-(hydroxy-lower alkyl)-amino, alkyleneimino with 4 to 8 carbon atoms, piperazino, 4-lower alkyl-piperazino, 4- morpholino and 4-thiamorpholino, acid addition salts thereof and lower alkyl quaternary ammonium salts thereof.

9. A member selected from the group consisting of his [4 (3 dimethylamino propoxy) 2 methyl 5- tert. butyl-phenyH-sulfide and an acid addition salt thereof.

10. A member selected from the group consisting of bis [2 (3 dimethylamino propoxy) 5 methyl- 3-tert. butyl-phenyl1-sulfide and an acid addition salt thereof.

11. A member selected from the group consisting of his [4 (3 diethylamino propoxy) 2 methyl- S-tert. butyl-phenyl1-sulfide and an acid addition salt thereof.

No references cited.

ALEX MAZEL, Primary Examiner.

JOSE TOVAR, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,332,958 July 25, 1967 Lincoln Harvey Werner It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below Column 17, line 8, for "alnyl-amino" read alkylamino Signed and sealed this 28th day of January 1969.

(SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents Edward M. Fletcher, Jr.

Attesting Officer 

3. A MEMBER SELECTED FROM THE GROUP CONSISTING OF BIS - (4- (3 - DIMETHYLAMINO -PROPOXY) - 3 - METHYL - 5TERT. BUTYL-PHENYL)-SULFIDE AND AN ACID ADDITION SALT THEREOF.
 11. A MEMBER SELECTED FROM THE GROUP CONSISTING OF BIS - (4 - (3 - DIETHYLAMINO - PROPOXY) - 2 - METHYL5-TERT. BUTYL-PHENYL)-SULFIDE AND AN ACID ADDITION SALT THEREOF. 